EP1163909B1 - Use of sugar ethers as immunity adjuvant in vaccine compositions, therapeutic compositions containing them and their use as vaccine - Google Patents
Use of sugar ethers as immunity adjuvant in vaccine compositions, therapeutic compositions containing them and their use as vaccine Download PDFInfo
- Publication number
- EP1163909B1 EP1163909B1 EP01401415A EP01401415A EP1163909B1 EP 1163909 B1 EP1163909 B1 EP 1163909B1 EP 01401415 A EP01401415 A EP 01401415A EP 01401415 A EP01401415 A EP 01401415A EP 1163909 B1 EP1163909 B1 EP 1163909B1
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- European Patent Office
- Prior art keywords
- composition
- formula
- compound
- radical
- water
- Prior art date
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- 229960005486 vaccine Drugs 0.000 title description 14
- 150000002170 ethers Chemical class 0.000 title 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to novel adjuvants for vaccine compositions as well as compositions comprising at least one antigen, in particular an antigen of viral, bacterial or parasitic origin and at least one adjuvant.
- Immune adjuvants are products that enhance immune system reactions when administered in the presence of antigens of viral, bacterial or parasitic origin. They cause the massive appearance of macrophages at the injection site, then in lymphatic nodules, increase the production of specific immunoglobulins, antibodies, and stimulate many cells involved in the mechanisms of immune defense.
- adjuvants are of various natures. They may for example consist of mixtures of oils and surfactants leading to vaccines in the form of liposomes or emulsions.
- Freund's adjuvants are very effective; they result from the combination of a mineral oil and a mannitol ester containing or not killed mycobacterium.
- Vaccines made by equal mixing between Freund's adjuvant and an aqueous antigenic medium are still world-wide references for laboratory studies. They are in the form of water-in-oil emulsions (W / O), ie emulsions in which the continuous phase is the oil. However, these emulsions are very viscous and are therefore difficult to inject. They are also unstable, since phase shifts are observed only a few days after their preparation.
- metal salts such as aluminum hydroxide, cerium nitrate, zinc sulfate, colloidal iron hydroxide or calcium chloride.
- aluminum hydroxide is the most commonly used.
- adjuvants are described in the article of Rajesh K. Gupta et al. Adjuvants, balance between toxicity and adjuvanticity, Vaccine, vol. 11, Issue 3, 1993, pp. 293-306 . However, they have a low immunostimulatory efficiency and sometimes, when these therapeutic compositions are injected, the formation of lesions and other local reactions, such as granulomas, at the injection site.
- adjuvants of immunity especially in the case of mucosal administration, include the sympathomimetic compounds described in the international patent application published under the number WO 98/15288 .
- R 1 -O- (G) x -H in which R 1 represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 1 to 30 carbon atoms, G represents the residue of a saccharide and x represents a decimal number between 1 and 5 or a mixture of compounds of formula (I) as an immunity adjuvant in a vaccine composition comprising at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence.
- residue of a saccharide is meant for G, a divalent radical resulting from the removal on a molecule of sugar, on the one hand of a hydrogen atom of one of its hydroxyl groups and on the other hand of anomeric hydroxyl group.
- saccharide refers in particular to glucose or dextrose, fructose, mannose, galactose, altrose, idose, arabinose, xylose, ribose, gulose, lyxose, maltose, maltotriose, lactose, cellobiose, dextran, talose, allose, raffinose, levoglucan, cellulose or starch.
- the oligomeric structure (G) x can be in any form of isomerism, whether it is optical isomerism, geometric isomerism or isomerism of position, it can also represent a mixture of isomers.
- the number x which represents in the formula (I) the average degree of polymerization of the saccharide, is more particularly between 1 and 3, in particular between 1.05 and 2.5, in particular between 1.1 and 2.0, and preferably, less than or equal to 1.5.
- G represents more particularly the rest of the glucose or the rest of the xylose.
- the radical R 1 represents in particular a radical containing from 5 to 22 carbon atoms chosen from the radicals pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, unicosyl, docosyl, heptadecenyl, eicosenenyl, unicosenenyl, docosenyl or heptadecadienyl or decenyl, said radicals being linear or branched.
- R 1 preferably represents a radical comprising from 8 to 20 carbon atoms, said radicals being linear or branched.
- R 2 represents more particularly a radical containing from 8 to 22 carbon atoms chosen from radicals, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, unicosyl, docosyl, heptadecenyl, eicosenyl, unicosenyl, docosenyl or heptadecadienyl or decenyl, said radicals being linear or branched.
- antigen or at least one in vivo generator of a compound comprising an amino acid sequence denotes either killed microorganisms, such as viruses, bacteria or parasites, or purified fractions of these microorganisms, or living micro-organisms whose pathogenicity has been reduced.
- killed microorganisms such as viruses, bacteria or parasites, or purified fractions of these microorganisms, or living micro-organisms whose pathogenicity has been reduced.
- viruses that can constitute an antigen according to the present invention mention may be made of rabies virus, herpes viruses, such as Aujeszky's disease virus, orthomixoviruses such as Influenzae, picornaviruses such as foot-and-mouth disease or retroviruses such as HIV.
- microorganisms of the bacterial type which may constitute an antigen according to the present invention mention may be made of E.
- viruses in particular non-enveloped viruses such as adenoviruses, vaccinia virus, Canarypox virus, herpesviruses or baculoviruses.
- a live non-enveloped viral recombinant vector the genome of which contains, preferably inserted into a non-essential portion for replication of the corresponding enveloped virus, a sequence encoding an antigenic subunit inducing antibody synthesis and / or a protective effect against the aforesaid enveloped virus or pathogenic micro-organism; these antigenic subunits may be, for example, a protein, a glycoprotein, a peptide or a peptide and / or protective fraction against infection with a living microorganism such as an enveloped virus, a bacterium or a parasite.
- the exogenous gene inserted in the microorganism may be, for example, derived from an Aujeszky or HIV virus.
- the subject of the present invention is the use as defined above, in a vaccine composition
- a vaccine composition comprising an aqueous phase and one or more oils chosen from mineral, animal or vegetable oils, in a proportion by weight in the oily phase, comprised in 10% and 90% of its total weight and preferably between 30% and 70% by weight of its total weight
- the vaccine composition comprises an aqueous phase and an oily phase
- it is generally in the form of a water-in-oil emulsion (W / O), an oil-in-water (O / W) emulsion, a water-in-water emulsion.
- oil in water W / O / E or microemulsion.
- the weight ratio of compound of formula (I) / compound of formula (II) is generally between 10 / 90 and 90/10, more particularly between 10/90 and 60/40.
- composition as defined above may also comprise one or more oils chosen from mineral, animal or vegetable oils, in a weight proportion in the oily phase, comprised between 10 and 90% of its total weight and preferably between 30% and 70% by weight of its total weight.
- composition When the composition comprises an aqueous phase and an oily phase, it is generally in the form of a water-in-oil emulsion (W / O), an oil-in-water (O / W) emulsion, a water-in-water emulsion. oil in water (W / O / E) or microemulsion.
- W / O water-in-oil emulsion
- O / W oil-in-water
- oil in water oil in water
- microemulsion oil in water
- composition as defined above may also comprise an aqueous phase and not comprise an oily phase.
- a composition according to the invention comprises an antigen concentration which depends on the nature of this antigen and the nature of the subject being treated. It is however particularly remarkable that an adjuvant according to the invention makes it possible to significantly reduce the usual dose of antigen required.
- the adequate concentration of antigen can be determined in a conventional manner by those skilled in the art. Generally, this dose is of the order of 0.1 ⁇ g / cm 3 to 1 g / cm 3 more generally between 1 ⁇ g / cm 3 and 100 mg / cm 3 .
- the concentration of said in vivo generator in the composition according to the invention again depends, in particular, on the nature of said generator and the host in which it is administered. This concentration can be readily determined by those skilled in the art based on routine experience. As an indication, we can however, that when the generator in vivo is a recombinant microorganism, its concentration in the composition of the invention may be between 10 2 and 10 15 microorganisms / cm 3, preferably between 10 5 and 10-organisms Micro 12 / cm 3 . When the in vivo generator is a recombinant plasmid, its concentration in the composition is between 0.01 mg and 100 mg / cm 3 .
- a composition according to the present invention contains between 0.2 mg / cm 3 and 500 mg / cm 3 of adjuvant, more particularly between 2 mg / cm 3 and 500 mg / cm 3 of adjuvant and preferably between 50 mg / cm 3 and 200 mg / cm 3 of adjuvant.
- the compounds of formulas (I) and (II) are preferably pharmaceutically acceptable and well tolerated by the human or animal body; they must in particular be free of heavy metals and have very low acid or peroxide levels. It is also desirable that they meet the standards determined by safety tests, including those described by SS Berllin, Annals of Allergy, 1962, 20, 473 or those described in the European Pharmacopoeia.
- composition according to the invention may also comprise a conventional immune stimulating agent such as Avridine TM , N, N-dioctadecyl-N ', N'-bis (2-hydroxyethyl) propanediamine, and the derivatives of MDP (muramyl dipeptide). , especially threonyl-MDP, mycolic acid derivatives or Lipid A derivatives.
- a conventional immune stimulating agent such as Avridine TM , N, N-dioctadecyl-N ', N'-bis (2-hydroxyethyl) propanediamine, and the derivatives of MDP (muramyl dipeptide).
- MDP muramyl dipeptide
- composition according to the invention may also comprise one or more organic salts of water-soluble metal cations, such as, for example, calcium gluconate, manganese gluconate, manganese glycerophosphate, calcium glycerophosphate, calcium fructoheptonate, Manganese fructoheptonate, aluminum salicylate or soluble aluminum acetate.
- organic salts of water-soluble metal cations such as, for example, calcium gluconate, manganese gluconate, manganese glycerophosphate, calcium glycerophosphate, calcium fructoheptonate, Manganese fructoheptonate, aluminum salicylate or soluble aluminum acetate.
- the adjuvant composition according to the invention comprises one or more salts, it is at a concentration of 0.02 to 3000 mg / cm 3 , preferably 0.1 mg to 1000 mg / cm 3 , more preferably 0, 1 mg to 150 mg / cm 3 .
- the composition according to the invention may comprise a sympathomimetic compound.
- Sympathomimetic compounds are especially amphetamines, catecholamines, phenylisopropylamines or tyramine.
- examples of such compounds include isoproterenol, L-Epinephrine, levarterenol, ephedrine, phenylephedrine or salbutamol.
- the adjuvant composition according to the invention comprises a sympathomimetic compound, it is at a concentration of 10 -10 molar to 10 -2 molar, preferably 10 -7 molar to 10 -5 molar.
- composition according to the invention may be used as a preventive or curative medicament.
- a composition according to the invention can be administered to fish, crustaceans such as shrimp, poultry, in particular, geese, turkeys, pigeons and chickens, to canids such as dogs, felids such as cats, pigs, primates, cattle, ovids and horses.
- the composition according to the invention can also be administered to humans.
- the administration of the composition may be conventionally carried out parenterally, in particular by subcutaneous, intramuscular or intraperitoneal injection or by the mucosal route, especially orally, rectally, nasally or vaginally.
- this consists in the use of an adjuvant as defined above for the preparation of a vaccine intended for the prevention or treatment of an infectious disease, in particular an illness infectious caused by a virus or micro-organism such as those mentioned above.
- this consists in the use of this adjuvant for the preparation of a composition intended to cure a disease of a functional order, such as cancer or cystic fibrosis.
- composition% by weight Alkyl polyglucosides of formula (I) Alcohols of formula (II) Water composition (A) ⁇ 12% R 1 in C 16 and C 18 ⁇ 87% R 2 in C 16 and C 18 0% composition (B) ⁇ 14.5% R 1 in C 12 + ⁇ 19% R 1 to C 14 + ⁇ 11% R 1 in C 16 + ⁇ 21.5% R 1 in C 18 ⁇ 1.5% R 2 in C 14 + ⁇ 4.5% R 2 in C 16 + ⁇ 28% R 2 in C 18 0% Composition C 50-55% R 1 in C 10 -C 14 ⁇ 5% 40-45% Composition D ⁇ 14.5% R 1 isostearyl ⁇ 85.5% R 2 isostearyl 0% Composition E ⁇ 11% R 1 isostearyl ⁇ 90% R 2 isostearyl 0% Composition F ⁇ 16.5% R 1 oleyl ⁇ 83.5% R 2 Oleyl 0%
- the injected compositions are the following: injected compositions fatty phase PBS Ovalbumin 0.1 mg / cm 3 composition 1 1 ml containing 10% composition D + 90% of MARCOL TM 52 1 ml 20 ⁇ l composition 2 1 ml containing 10% composition E + 90% of MARCOL TM 52 1 ml 20 ⁇ l composition 3 1 ml containing 10% composition F + 90% of MARCOL TM 52 1 ml 20 ⁇ l witness 1 ml of MARCOL TM 52 1 ml 20 ⁇ l
- the results of the ELISA tests are as follows: Assay of IgG1 (time scale in days) injected composition J14 D28 D42 D56 J90 composition 1 30000 300000 1000000 700000 700000 composition 2 30000 300000 1000000 1000000 700000 Composition 3 15000 100000 900000 600000 700000 witness 0 0 80000 15000 15000 Assay of IgG2 (time scale in days) injected composition J14 D28 D42 D56 J90 composition 1 ⁇ 1000 2500 100000 30000 9000 composition 2 ⁇ 1000 6000 100000 50000 30000 Composition 3 ⁇ 1000 6000 100000 50000 30000 witness ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000 ⁇ 1000
- the injected compositions are the following: injected compositions adjuvant PBS BSA composition 4 0.2 ml of a solution in PBS, comprising 10% by weight of the composition A. 1.8 ml 0.02 ml composition 5 0.02 ml of a solution in PBS, comprising 14.3% by weight of composition B. 1.98 ml 0.02 ml composition 6 0.02 ml of a solution in PBS, comprising 20% by weight of the composition C. 1.98 ml 0, 02 ml composition 7 2 ml of a solution in PBS, comprising 10% by weight of the composition A.
- composition 8 0.2 ml of a solution in PBS, comprising 14.3% by weight of composition B.
- 1.8 ml 0.02 ml composition 9 0.2 ml of a solution in PBS, comprising 20% by weight of the composition C.
- 1.8 ml 0.02 ml Witness 0 2ml 0.02 ml
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Description
La présente invention concerne de nouveaux adjuvants pour compositions vaccinales ainsi que des compositions comprenant au moins un antigène, notamment un antigène d'origine virale, bactérienne ou parasitaire et au moins un adjuvant.The present invention relates to novel adjuvants for vaccine compositions as well as compositions comprising at least one antigen, in particular an antigen of viral, bacterial or parasitic origin and at least one adjuvant.
Le développement de vaccins inactivés ou contenant des antigènes purifiés est de plus en plus important, car il permet d'éviter les effets secondaires indésirables. Cependant, l'amélioration de la qualité des antigènes se fait au détriment de leur caractère immunogène. C'est pour cette raison qu'ils sont associés à des adjuvants d'immunité.The development of vaccines inactivated or containing purified antigens is increasingly important because it avoids undesirable side effects. However, the improvement of the quality of the antigens is to the detriment of their immunogenic character. It is for this reason that they are associated with immunity adjuvants.
Les adjuvants d'immunité sont des produits qui augmentent les réactions du système immunitaire, lorsqu'ils sont administrés en présence d'antigènes d'origine virale, bactérienne ou parasitaire. Ils provoquent l'apparition massive de macrophages au site d'injection, puis dans les nodules lymphatiques, accroissent la production d'immunoglobulines spécifiques, les anticorps, et stimulent de nombreuses cellules impliquées dans les mécanismes de la défense immunitaire.Immune adjuvants are products that enhance immune system reactions when administered in the presence of antigens of viral, bacterial or parasitic origin. They cause the massive appearance of macrophages at the injection site, then in lymphatic nodules, increase the production of specific immunoglobulins, antibodies, and stimulate many cells involved in the mechanisms of immune defense.
Ces adjuvants sont de natures diverses. Ils peuvent par exemple consister en des mélanges d'huiles et de tensioactifs conduisant à des vaccins sous forme de liposomes ou d'émulsions.These adjuvants are of various natures. They may for example consist of mixtures of oils and surfactants leading to vaccines in the form of liposomes or emulsions.
Les adjuvants de Freund sont très efficaces ; ils résultent de l'association d'une huile minérale et d'un ester de mannitol contenant ou non une mycobactérie tuée.Freund's adjuvants are very effective; they result from the combination of a mineral oil and a mannitol ester containing or not killed mycobacterium.
Les vaccins réalisés par mélange à parts égales, entre un adjuvant de Freund et un milieu antigénique aqueux, restent encore les références dans le monde entier pour les études en laboratoire. Ils se présentent sous forme d'émulsions eau dans huile (E/H), c'est à dire d'émulsions dans lesquelles la phase continue est l'huile. Or, ces émulsions sont très visqueuses et sont donc difficilement injectables. Elles sont aussi peu stables, puisque des déphasages sont observés quelques jours seulement, après leur préparation.Vaccines made by equal mixing between Freund's adjuvant and an aqueous antigenic medium are still world-wide references for laboratory studies. They are in the form of water-in-oil emulsions (W / O), ie emulsions in which the continuous phase is the oil. However, these emulsions are very viscous and are therefore difficult to inject. They are also unstable, since phase shifts are observed only a few days after their preparation.
Comme adjuvants usuels, il y a aussi des sels de métaux, tels que l'hydroxyde d'aluminium, le nitrate de cérium, le sulfate de zinc, l'hydroxyde de fer colloïdal ou le chlorure de calcium. Parmi ceux-ci, l'hydroxyde d'aluminium est le plus couramment utilisé. Ces adjuvants sont décrits dans l'article de
On a découvert plus récemment, que les sels hydrosolubles de métaux divalents ou trivalents, étaient de bons adjuvants de l'immunité. Parmi ceux-ci, le gluconate de manganèse, le gluconate de calcium, le glycérophosphate de manganèse, l'acétate d'aluminium soluble ou le salicylate d'aluminium sont les plus prometteurs. De tels adjuvants sont décrits dans les demandes internationales de brevet publiées sous les numéros
Comme autres adjuvants de l'immunité, notamment dans le cas de l'administration mucosale, on peut citer les composés sympathomimétiques décrits dans la demande internationale de brevet publiée sous le numéro
A l'occasion de recherches sur la mise au point de nouveaux adjuvants, la demanderesse a découvert que certains agents tensioactifs eux-mêmes, possédaient une efficacité immunostimulante en l'absence d'huiles, et que l'on pouvait ainsi préparer des compositions vaccinales aqueuses, comprenant un ou plusieurs de ces agents comme immunostimulants.In the course of research on the development of new adjuvants, the Applicant has discovered that certain surfactants themselves, had an immunostimulatory efficacy in the absence of oils, and that it was thus possible to prepare vaccine compositions aqueous, comprising one or more of these agents as immunostimulants.
C'est pourquoi, l'invention a pour objet, l'utilisation d'un composé de formule (I) :
R1-O-(G)x-H (I)
dans laquelle R1 représente un radical hydrocarboné linéaire ou ramifié, saturé ou insaturé comprenant de 1 à 30 atomes de carbones, G représente le reste d'un saccharide et x représente un nombre décimal compris entre 1 et 5 ou un mélange de composés de formule (I), comme adjuvant d'immunité dans une composition vaccinale comprenant au moins un antigène ou au moins un générateur in vivo d'un composé comprenant une séquence d'acides aminés.This is why the subject of the invention is the use of a compound of formula (I):
R 1 -O- (G) x -H (I)
in which R 1 represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 1 to 30 carbon atoms, G represents the residue of a saccharide and x represents a decimal number between 1 and 5 or a mixture of compounds of formula (I) as an immunity adjuvant in a vaccine composition comprising at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence.
Par reste d'un saccharide, on désigne pour G, un radical bivalent résultant de l'enlèvement sur une molécule de sucre, d'une part d'un atome d'hydrogène d'un de ses groupes hydroxyle et d'autre part du groupe hydroxyle anomérique. Le terme saccharide désigne notamment le glucose ou dextrose, le fructose, le mannose, le galactose, l'altrose, l'idose, l'arabinose, le xylose, le ribose, le gulose, le lyxose, le maltose, le maltotriose, le lactose, le cellobiose, le dextrane, le talose, l'allose, le raffinose, le lévoglucane, la cellulose ou l'amidon. La structure oligomérique (G)x peut se présenter sous toute forme d'isomérie, qu'il s'agisse d'isomérie optique, d'isomérie géométrique ou d'isomérie de position, elle peut aussi représenter un mélange d'isomères.By residue of a saccharide is meant for G, a divalent radical resulting from the removal on a molecule of sugar, on the one hand of a hydrogen atom of one of its hydroxyl groups and on the other hand of anomeric hydroxyl group. The term saccharide refers in particular to glucose or dextrose, fructose, mannose, galactose, altrose, idose, arabinose, xylose, ribose, gulose, lyxose, maltose, maltotriose, lactose, cellobiose, dextran, talose, allose, raffinose, levoglucan, cellulose or starch. The oligomeric structure (G) x can be in any form of isomerism, whether it is optical isomerism, geometric isomerism or isomerism of position, it can also represent a mixture of isomers.
Le nombre x, qui représente dans la formule (I) le degré moyen de polymérisation du saccharide, est plus particulièrement compris entre 1 et 3, notamment entre 1,05 et 2,5, tout particulièrement entre 1,1 et 2,0 et de préférence, inférieur ou égal à 1,5.The number x, which represents in the formula (I) the average degree of polymerization of the saccharide, is more particularly between 1 and 3, in particular between 1.05 and 2.5, in particular between 1.1 and 2.0, and preferably, less than or equal to 1.5.
G représente plus particulièrement le reste du glucose ou le reste du xylose.G represents more particularly the rest of the glucose or the rest of the xylose.
Le radical R1 représente notamment un radical comportant de 5 à 22 atomes de carbone choisi parmi les radicaux pentyle, hexyle, heptyle, octyle, nonyle, décyle, undécyle, dodécyle, tridécyle, tétradécyle, pentadécyle, hexadécyle, heptadécyle, octadécyle, nonadécyle, eicosyle, uneicosyle, docosyle, heptadécènyle, eicosènyle, uneicosènyle, docosènyle ou heptadécadiènyle ou décènyle, lesdits radicaux étant linéaires ou ramifiés. R1 représente de préférence un radical comportant de 8 à 20 atomes de carbone lesdits radicaux étant linéaires ou ramifiés.The radical R 1 represents in particular a radical containing from 5 to 22 carbon atoms chosen from the radicals pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, unicosyl, docosyl, heptadecenyl, eicosenenyl, unicosenenyl, docosenyl or heptadecadienyl or decenyl, said radicals being linear or branched. R 1 preferably represents a radical comprising from 8 to 20 carbon atoms, said radicals being linear or branched.
R2 représente plus particulièrement un radical comportant de 8 à 22 atomes de carbone choisi parmi les radicaux, octyle, nonyle, décyle, undécyle, dodécyle, tridécyle, tétradécyle, pentadécyle, hexadécyle, heptadécyle, octadécyle, nonadécyle, eicosyle, uneicosyle, docosyle, heptadécènyle, eicosènyle, uneicosènyle, docosènyle ou heptadécadiènyle ou décènyle, lesdits radicaux étant linéaires ou ramifiés.R 2 represents more particularly a radical containing from 8 to 22 carbon atoms chosen from radicals, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, unicosyl, docosyl, heptadecenyl, eicosenyl, unicosenyl, docosenyl or heptadecadienyl or decenyl, said radicals being linear or branched.
Par antigène ou au moins un générateur in vivo d'un composé comprenant une séquence d'acides aminés, on désigne soit des microorganismes tués, tels que les virus, les bactéries ou les parasites, soit des fractions purifiées de ces micro-organismes, soit des micro-organismes vivants dont le pouvoir pathogène a été atténué. A titre de virus pouvant constituer un antigène selon la présente invention, on peut citer le virus de la rage, les herpès virus, tels que le virus de la maladie d'Aujeszky, les orthomixovirus tels que Influenzae, les picornavirus tels que le virus de la fièvre aphteuse ou les rétrovirus tels que les VIH. A titre de micro-organisme du type bactérien pouvant constituer un antigène selon la présente invention, on peut citer E. Coli, et ceux des genres Pasteurella, Furonculosis, Vibriosis, Staphylococcus et Streptococcus. A titre de parasite, on peut citer ceux des genres Trypanosoma, Plasmodium et Leishmania. On peut aussi citer les virus recombinants notamment les virus non enveloppés tels que les adénovirus, le virus de la vaccine, le virus Canarypox, les herpès virus ou les baculovirus. On désigne aussi un vecteur recombinant viral non enveloppé vivant, dont le génome contient, insérée de préférence dans une partie non essentielle pour la réplication du virus enveloppé correspondant, une séquence codant pour une sous-unité antigénique induisant une synthèse d'anticorps et/ou un effet protecteur contre le susdit virus enveloppé ou micro-organisme pathogène ; ces sous-unités antigéniques peuvent être par exemple, une protéine, une glycoprotéine, un peptide ou une fraction peptidique et/ou protectrice contre une infection par un micro-organisme vivant tel un virus enveloppé, une bactérie ou un parasite. Le gène exogène inséré dans le micro-organisme peut être, par exemple, issu d'un virus Aujeszky ou HIV.By antigen or at least one in vivo generator of a compound comprising an amino acid sequence, denotes either killed microorganisms, such as viruses, bacteria or parasites, or purified fractions of these microorganisms, or living micro-organisms whose pathogenicity has been reduced. As viruses that can constitute an antigen according to the present invention, mention may be made of rabies virus, herpes viruses, such as Aujeszky's disease virus, orthomixoviruses such as Influenzae, picornaviruses such as foot-and-mouth disease or retroviruses such as HIV. As microorganisms of the bacterial type which may constitute an antigen according to the present invention, mention may be made of E. coli, and those of the genera Pasteurella, Furunculosis, Vibriosis, Staphylococcus and Streptococcus. As a parasite, mention may be made of the genera Trypanosoma, Plasmodium and Leishmania. It is also possible to mention recombinant viruses, in particular non-enveloped viruses such as adenoviruses, vaccinia virus, Canarypox virus, herpesviruses or baculoviruses. Also meant is a live non-enveloped viral recombinant vector, the genome of which contains, preferably inserted into a non-essential portion for replication of the corresponding enveloped virus, a sequence encoding an antigenic subunit inducing antibody synthesis and / or a protective effect against the aforesaid enveloped virus or pathogenic micro-organism; these antigenic subunits may be, for example, a protein, a glycoprotein, a peptide or a peptide and / or protective fraction against infection with a living microorganism such as an enveloped virus, a bacterium or a parasite. The exogenous gene inserted in the microorganism may be, for example, derived from an Aujeszky or HIV virus.
On peut citer notamment un plasmide recombinant constitué d'une séquence de nucléotides, dans laquelle est insérée une séquence nucléotidique exogène, provenant d'un micro-organisme ou d'un virus pathogène. Cette dernière séquence nucléotidique a pour but de permettre l'expression d'un composé comprenant une séquence d'acides aminés, ce composé ayant lui-même pour but de déclencher une réaction immune dans un organisme hôte. Par générateur "in vivo" d'un composé comprenant une séquence d'acides aminés, on désigne tout produit biologique capable d'exprimer ledit composé dans l'organisme hôte dans lequel on a introduit ledit générateur in vivo. Le composé comprenant la séquence d'acides aminés, peut être une protéine, un peptide ou une glycoprotéine. Ces générateurs in vivo sont généralement obtenus par des procédés issus du génie génétique. Plus particulièrement, ils peuvent consister en des micro-organismes vivants, généralement un virus, jouant le rôle de vecteur recombinant, dans lequel est insérée une séquence nucléotidique, notamment un gène exogène. Ces composés sont connus en tant que tels et utilisés notamment comme vaccin sous unitaire recombinant. A cet égard, on peut se référer à l'Article de
- (i) être un antigène, et permettre le déclenchement d'une réaction immune, leukine 2. Celles-ci permettent le déclenchement ou le renforcement d'une réaction immune visant à l'élimination sélective des cellules cancéreuses.
- (i) be an antigen, and allow the triggering of an immune reaction, leukine 2. These allow the triggering or strengthening of an immune reaction aimed at the selective elimination of cancer cells.
Selon un premier aspect particulier de la présente invention, celle-ci a pour objet, l'utilisation telle que définie précédemment, dans une composition vaccinale comprenant une phase aqueuse et une ou plusieurs huiles choisies parmi les huiles minérales, animales ou végétales, dans une proportion pondérale en phase huileuse, comprise en 10% et 90% de son poids total et de préférence entre 30% et 70% en poids de son poids totalAccording to a first particular aspect of the present invention, the subject of the present invention is the use as defined above, in a vaccine composition comprising an aqueous phase and one or more oils chosen from mineral, animal or vegetable oils, in a proportion by weight in the oily phase, comprised in 10% and 90% of its total weight and preferably between 30% and 70% by weight of its total weight
Lorsque la composition vaccinale comprend une phase aqueuse et une phase huileuse, elle est généralement sous forme d'une émulsion eau dans huile (E/H), d'une émulsion huile dans eau (H/E), d'une émulsion eau dans huile dans eau (E/H/E) ou d'une microémulsion.When the vaccine composition comprises an aqueous phase and an oily phase, it is generally in the form of a water-in-oil emulsion (W / O), an oil-in-water (O / W) emulsion, a water-in-water emulsion. oil in water (W / O / E) or microemulsion.
Selon un deuxième aspect particulier de la présente invention, celle-ci a pour objet, l'utilisation d'un mélange comprenant :
- a) un composé de formule (I):
R1-O-(G)x-H (I)
telle que définie précédemment, ou un mélange de composés de formule (I), et si désiré - b) un composé de formule (II) :
R2-OH (II)
- a) a compound of formula (I):
R 1 -O- (G) x -H (I)
as defined above, or a mixture of compounds of formula (I), and if desired - b) a compound of formula (II):
R 2 -OH (II)
L'invention a aussi pour objet une composition sous forme d'une phase aqueuse comprenant :
- (i) au moins un antigène ou au moins un générateur in vivo d'un composé comprenant une séquence d'acides aminés et,
- (ii) au moins un composé de formule (I) :
R1-O-(G)x-H (I)
et si désiré - (iii) au moins un composé de formule (II),
pour laquelle les formules (I) et (II) ont les significations indiquées précédemment.
- (i) au moins un antigène ou au moins un générateur in vivo d'un composé comprenant une séquence d'acides aminés et,
- (ii) au moins un composé de formule (I)
R1-O-(G)x-H (I)
et - (iii) au moins un composé de formule (II),
- (i) at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence and,
- (ii) at least one compound of formula (I):
R 1 -O- (G) x -H (I)
and if desired - (iii) at least one compound of formula (II),
for which formulas (I) and (II) have the meanings indicated above.
- (i) at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence and,
- (ii) at least one compound of formula (I)
R 1 -O- (G) x -H (I)
and - (iii) at least one compound of formula (II),
Lorsque la composition telle que définie précédemment comporte au moins un composé de formule (I) et au moins un composé de formule (II), le rapport pondéral composé de formule (I) / composé de formule (II) est généralement compris entre 10 / 90 et 90 / 10, plus particulièrement entre 10 / 90 et 60 / 40.When the composition as defined above comprises at least one compound of formula (I) and at least one compound of formula (II), the weight ratio of compound of formula (I) / compound of formula (II) is generally between 10 / 90 and 90/10, more particularly between 10/90 and 60/40.
La composition telle que définie précédemment, peut comprendre en outre une ou plusieurs huiles choisies parmi les huiles minérales, animales ou végétales, dans une proportion pondérale en phase huileuse, comprise en 10 et 90% de son poids total et de préférence entre 30% et 70% en poids de son poids total.The composition as defined above may also comprise one or more oils chosen from mineral, animal or vegetable oils, in a weight proportion in the oily phase, comprised between 10 and 90% of its total weight and preferably between 30% and 70% by weight of its total weight.
Lorsque la composition comprend une phase aqueuse et une phase huileuse, elle est généralement sous forme d'une émulsion eau-dans huile (E/H), d'une émulsion huile dans eau (H/E), d'une émulsion eau dans huile dans eau (E/H/E) ou d'une microémulsion.When the composition comprises an aqueous phase and an oily phase, it is generally in the form of a water-in-oil emulsion (W / O), an oil-in-water (O / W) emulsion, a water-in-water emulsion. oil in water (W / O / E) or microemulsion.
Une composition telle que définie précédemment, peut aussi comprendre une phase aqueuse et ne pas comprendre de phase huileuse.A composition as defined above may also comprise an aqueous phase and not comprise an oily phase.
Une composition selon l'invention comprend une concentration en antigène qui dépend de la nature de cet antigène et de la nature du sujet traité. Il est toutefois particulièrement remarquable qu'un adjuvant selon l'invention, permette de diminuer notablement la dose habituelle d'antigène requise. La concentration adéquate d'antigène peut être déterminée de manière classique par l'homme du métier. Généralement, cette dose est de l'ordre de 0,1 µg / cm3 à 1 g / cm3 plus généralement comprise entre 1 µg / cm3 et 100 mg / cm3.A composition according to the invention comprises an antigen concentration which depends on the nature of this antigen and the nature of the subject being treated. It is however particularly remarkable that an adjuvant according to the invention makes it possible to significantly reduce the usual dose of antigen required. The adequate concentration of antigen can be determined in a conventional manner by those skilled in the art. Generally, this dose is of the order of 0.1 μg / cm 3 to 1 g / cm 3 more generally between 1 μg / cm 3 and 100 mg / cm 3 .
La concentration dudit générateur in vivo dans la composition selon l'invention dépend, là encore, notamment de la nature dudit générateur et de l'hôte dans lequel il est administré. Cette concentration peut être aisément déterminée par l'homme du métier, sur la base d'expérience de routine. A titre indicatif, on peut toutefois préciser que lorsque le générateur in vivo est un microorganisme recombinant, sa concentration dans la composition selon l'invention peut être comprise entre 102 et 1015 micro-organismes / cm3, de préférence entre 105 et 1012 micro-organismes / cm3. Lorsque le générateur in vivo est un plasmide recombinant, sa concentration dans la composition est comprise entre 0,01 mg et 100 mg / cm3.The concentration of said in vivo generator in the composition according to the invention again depends, in particular, on the nature of said generator and the host in which it is administered. This concentration can be readily determined by those skilled in the art based on routine experience. As an indication, we can however, that when the generator in vivo is a recombinant microorganism, its concentration in the composition of the invention may be between 10 2 and 10 15 microorganisms / cm 3, preferably between 10 5 and 10-organisms Micro 12 / cm 3 . When the in vivo generator is a recombinant plasmid, its concentration in the composition is between 0.01 mg and 100 mg / cm 3 .
Une composition objet de la présente invention, contient entre 0,2 mg / cm3 et 500 mg / cm3 d'adjuvant, plus particulièrement entre 2 mg / cm3 et 500 mg / cm3 d'adjuvant et de préférence entre 50 mg / cm3 et 200 mg / cm3 d'adjuvant.A composition according to the present invention contains between 0.2 mg / cm 3 and 500 mg / cm 3 of adjuvant, more particularly between 2 mg / cm 3 and 500 mg / cm 3 of adjuvant and preferably between 50 mg / cm 3 and 200 mg / cm 3 of adjuvant.
Les composés de formules (I) et (II) sont de préférence pharmaceutiquement acceptables et bien tolérés par l'organisme humain ou animal ; ils doivent notamment être dépourvus de métaux lourds et présenter des indices d'acides ou de peroxydes très faibles. Il est également souhaitable qu'ils satisfassent aux normes déterminées par des tests d'innocuité, notamment ceux décrits par
La composition selon l'invention, peut aussi comporter un agent stimulant immunitaire conventionnel tel l'Avridine™, la N,N-dioctadecyl-N',N'-bis(2-hydroxyéthyl) propanediamine, les dérivés du MDP (muramyl dipeptide), notamment le thréonyl-MDP, les dérivés de l'acide mycolique ou les dérivés du Lipide A.The composition according to the invention may also comprise a conventional immune stimulating agent such as Avridine ™ , N, N-dioctadecyl-N ', N'-bis (2-hydroxyethyl) propanediamine, and the derivatives of MDP (muramyl dipeptide). , especially threonyl-MDP, mycolic acid derivatives or Lipid A derivatives.
La composition selon l'invention, peut aussi comprendre un ou plusieurs sels organiques de cations métalliques hydrosolubles, tel que par exemple le gluconate de calcium, le gluconate de manganèse, le glycérophosphate de manganèse, le glycérophosphate de calcium, le fructoheptonate de calcium, le fructoheptonate de manganèse, le salicylate d'aluminium ou l'acétate d'aluminium soluble.The composition according to the invention may also comprise one or more organic salts of water-soluble metal cations, such as, for example, calcium gluconate, manganese gluconate, manganese glycerophosphate, calcium glycerophosphate, calcium fructoheptonate, Manganese fructoheptonate, aluminum salicylate or soluble aluminum acetate.
Lorsque la composition adjuvante selon l'invention comprend un ou plusieurs sels, celui-ci est à une concentration de 0,02 à 3000 mg / cm3, de préférence 0,1 mg à 1000 mg / cm3, plus préférentiellement de 0,1 mg à 150 mg / cm3. La composition selon l'invention, peut comprendre un composé sympathomimétique.When the adjuvant composition according to the invention comprises one or more salts, it is at a concentration of 0.02 to 3000 mg / cm 3 , preferably 0.1 mg to 1000 mg / cm 3 , more preferably 0, 1 mg to 150 mg / cm 3 . The composition according to the invention may comprise a sympathomimetic compound.
Par composés sympathomimétiques, on désigne notamment les amphétamines, les catécholamines, les phénylisopropylamines ou la tyramine. Comme exemples de tels composés, on peut citer notamment l'isoprotérénol, la L-Epinephrine, le lévartérénol, l'éphédrine, la phényléphédrine ou le salbutamol. Lorsque la composition adjuvante selon l'invention comprend un composé sympathomimétique, celui-ci est à une concentration de 10-10 molaire à 10-2 molaire, de préférence de 10-7 molaire à 10-5 molaire.Sympathomimetic compounds are especially amphetamines, catecholamines, phenylisopropylamines or tyramine. As examples of such compounds include isoproterenol, L-Epinephrine, levarterenol, ephedrine, phenylephedrine or salbutamol. When the adjuvant composition according to the invention comprises a sympathomimetic compound, it is at a concentration of 10 -10 molar to 10 -2 molar, preferably 10 -7 molar to 10 -5 molar.
La composition selon l'invention peut être utilisée comme médicament préventif ou curatif. Selon la nature de l'antigène ou du générateur in vivo, une composition selon l'invention peut être administrée à des poissons, des crustacés tels que les crevettes, des volailles, notamment, des oies, des dindes, des pigeons et des poulets, aux canidés tels le chien, aux félidés tels le chat, aux porcs, aux primates, aux bovidés, aux ovidés et aux chevaux. La composition selon l'invention peut être également administrée à l'homme. L'administration de la composition peut se faire de manière classique par voie parentérale, notamment par injection sous-cutanée, intramusculaire ou intrapéritonéale ou par voie mucosale notamment par voie orale, voie rectale, voie nasale, voie vaginale. Selon un autre aspect de l'invention, celle-ci consiste en l'utilisation d'un adjuvant tel que défini ci-dessus pour la préparation d'un vaccin destiné à la prévention ou au traitement d'une maladie infectieuse, notamment une maladie infectieuse engendrée par un virus ou un micro-organisme tels ceux mentionnés plus haut.The composition according to the invention may be used as a preventive or curative medicament. Depending on the nature of the antigen or the in vivo generator, a composition according to the invention can be administered to fish, crustaceans such as shrimp, poultry, in particular, geese, turkeys, pigeons and chickens, to canids such as dogs, felids such as cats, pigs, primates, cattle, ovids and horses. The composition according to the invention can also be administered to humans. The administration of the composition may be conventionally carried out parenterally, in particular by subcutaneous, intramuscular or intraperitoneal injection or by the mucosal route, especially orally, rectally, nasally or vaginally. According to another aspect of the invention, this consists in the use of an adjuvant as defined above for the preparation of a vaccine intended for the prevention or treatment of an infectious disease, in particular an illness infectious caused by a virus or micro-organism such as those mentioned above.
Selon un autre dernier aspect de la présente invention, celle-ci consiste en l'utilisation de cet adjuvant pour la préparation d'une composition destinée à soigner une maladie d'ordre fonctionnel, telle le cancer ou la mucoviscidose.According to another last aspect of the present invention, this consists in the use of this adjuvant for the preparation of a composition intended to cure a disease of a functional order, such as cancer or cystic fibrosis.
Les exemples suivants illustrent l'invention sans toutefois la limiter.The following examples illustrate the invention without limiting it.
Les tensioactifs utilisés sont les suivants :
~19% R1 en C14 +
~11 % R1 en C16 +
~21,5% R1 en C18
~4,5% R2 en C16 +
~28% R2 en C18
~ 19% R 1 to C 14 +
~ 11% R 1 in C 16 +
~ 21.5% R 1 in C 18
~ 4.5% R 2 in C 16 +
~ 28% R 2 in C 18
On a injecté par voie sous-cutanée, à différents lots de 5 souris femelles de souche OF1 ayant un poids moyen de 18 à 20 grammes, 100 microlitres de différentes compositions contenant un agent tensioactif une huile, du tampon phosphate (PBS) et 0,1 mg / cm3 d'ovalbumine, à t = 0 avec un rappel à t = 28 jours. On effectue les prélèvements sanguins à 14, 28, 42, 56 et 90 jours. On procède à des dosages ELISA sur les prélèvements sanguins, des IgG1 pour déterminer la réponse immunitaire humorale et les IgG2a, pour déterminer la réponse immunitaire cellulaire.Subsequently, subcutaneous injections of 100 microliters of different compositions containing a surfactant, an oil, phosphate buffer (PBS) and 0 were injected subcutaneously into different batches of female OF1 mice with an average weight of 18 to 20 grams. 1 mg / cm 3 of ovalbumin, at t = 0 with a booster at t = 28 days. Blood samples are taken at 14, 28, 42, 56 and 90 days. ELISA assays on blood samples, IgG1 to determine the humoral immune response and IgG2a are performed to determine the cellular immune response.
Les compositions injectées sont les suivantes :
Les résultats des tests ELISA sont les suivants :
On a injecté par voie sous-cutanée, à différents lots de 5 souris femelles de souche OF1 ayant un poids moyen de 18 à 20 grammes, 100 microlitres de différentes compositions contenant un agent tensioactif, du tampon phosphate (PBS) et 25 mg / cm3 d'albumine BSA, à t = 0 avec un rappel à t = 28 jours. On effectue les prélèvements sanguins à 14, 28, 42, 56, 90 et 180.joursSubsequently, subcutaneous injections of 100 microliters of various OF1 strain mice having an average weight of 18-20 grams were injected subcutaneously with 100 microliters of various surfactant-containing compositions, phosphate buffer (PBS) and 25 mg / cm. 3 BSA albumin, at t = 0 with a booster at t = 28 days. Blood samples are taken at 14, 28, 42, 56, 90 and 180 days
On procède à des dosages ELISA sur les prélèvements sanguins, des IgG1 pour déterminer la réponse immunitaire humorale et les IgG2a, pour déterminer la réponse immunitaire cellulaire. Les compositions injectées sont les suivantes :
Les résultats des tests ELISA sont les suivants :
Claims (17)
- Use of a compound of formula (I):
R1-O-(G)x-H (I)
in which R1 represents a saturated or unsaturated, linear or branched hydrocarbon-based radical comprising 1 to 30 carbon atoms, G represents the residue of a saccharide and x represents a decimal number between 1 and 5, or a mixture of compounds of formula (I), as an adjuvant of immunity in an immunization composition comprising at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence. - Use as defined in Claim 1, according to which, in formula (I), the number x is between 1 and 3, more particularly between 1.05 and 2.5, most particularly between 1.1 and 2.0, and preferably less than or equal to 1.5.
- Use as defined in either of Claims 1 and 2, according to which, in formula (I), G represents the residue of glucose or the residue of xylose.
- Use as defined in any one of Claims 1 to 3, according to which in formula (I), the R1 radical represents a radical comprising from 5 to 22 carbon atoms, chosen from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, uneicosyl, docosyl, heptadecenyl, eicosenyl, uneicosenyl, docosenyl or heptadecadienyl or decenyl radicals, said radicals being linear or branched.
- Use as defined in Claim 4, according to which, in formula (I), R1 represents a radical comprising from 8 to 20 carbon atoms, said radicals being linear or branched.
- Use as defined in any one of Claims 1 to 5, according to which, in formula (I), R2 represents a radical comprising from 8 to 22 carbon atoms, chosen from octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, uneicosyl, docosyl, heptadecenyl, eicosenyl, uneicosenyl, docosenyl or heptadecadienyl or decenyl radicals, said radicals being linear or branched.
- Use as defined in any one of Claims 1 to 6, an immunization composition comprising an aqueous phase and one or more oils chosen from mineral, animal or plant oils, in a weight proportion in oily phase of between 10 and 90% of the total weight thereof, and preferably between 30% and 70% by weight of the total weight thereof.
- Use as defined in any one of Claims 1 to 7, in an immunization composition comprising an aqueous phase and not comprising an oily phase.
- Composition comprising:(i) at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence and,(ii) at least one compound of formula (I):
R1-O- (G)x-H (I)
and,(iii) at least one compound of formula (II),in which R2 represents, independently of R1, a saturated or unsaturated, linear or branched hydrocarbon-based radical comprising from 8 to 30 carbon atoms,
R2-OH (II)
in which formula (I) is as defined in any one of Claims 1 to 6. - Composition as defined in Claim 9, also comprising one or more oils chosen from mineral, animal or plant oils, in a weight proportion in oily phase of between 10 and 90% of the total weight thereof, and preferably between 30% and 70% by weight of the total weight thereof.
- Composition as defined in Claim 10, in the form of a water-in-oil (W/O) emulsion, of an oil-in-water (O/W) emulsion, of a water-in-oil-in-water (W/O/W) emulsion or of a microemulsion.
- Composition as defined in Claim 9, not comprising an oily phase.
- Composition as defined in one of Claims 9 to 12, also comprising one or more water-soluble metal cation organic salts, such as for example calcium gluconate, manganese gluconate, manganese glycerophosphate, calcium glycerophosphate, calcium fructoheptonate, manganese fructoheptanate, aluminium salicylate or soluble aluminium acetate.
- Composition as defined in one of Claims 9 to 13, also comprising a sympathomimetic compound chosen from tyramine, isoproterenol, L-adrenaline, levarterenol, ephedrine, phenylephedrine or salbutamol.
- Composition as defined in one of Claims 9 to 14, for carrying out therapeutic treatment of the human or animal body.
- Composition as defined in Claim 15, for carrying out therapeutic treatment of the human or animal body via the parenteral pathway, by subcutaneous, intramuscular or intraperitoneal injection.
- Composition as defined in Claim 16, for carrying out therapeutic treatment of the human or animal body via the mucosal pathway, in particular orally, rectally, nasally or vaginally.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0007408A FR2809961B1 (en) | 2000-06-09 | 2000-06-09 | USE OF SUGAR ETHERS AS IMMUNITY ADDITIVES IN VACCINE COMPOSITIONS, THERAPEUTIC COMPOSITIONS CONTAINING THEM AND THEIR USE AS VACCINES |
| FR0007408 | 2000-06-09 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP1163909A2 EP1163909A2 (en) | 2001-12-19 |
| EP1163909A3 EP1163909A3 (en) | 2002-02-06 |
| EP1163909B1 true EP1163909B1 (en) | 2008-10-15 |
Family
ID=8851139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP01401415A Expired - Lifetime EP1163909B1 (en) | 2000-06-09 | 2001-05-31 | Use of sugar ethers as immunity adjuvant in vaccine compositions, therapeutic compositions containing them and their use as vaccine |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20020048587A1 (en) |
| EP (1) | EP1163909B1 (en) |
| JP (1) | JP2002020314A (en) |
| DE (1) | DE60136126D1 (en) |
| FR (1) | FR2809961B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019182745A1 (en) | 2018-03-19 | 2019-09-26 | Bryn Pharma, LLC | Epinephrine spray formulations |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2649013B1 (en) * | 1989-07-03 | 1991-10-25 | Seppic Sa | VACCINES AND VECTORS OF FLUID ACTIVE INGREDIENTS CONTAINING METABOLIZABLE OIL |
| FR2700957B1 (en) * | 1993-01-29 | 1995-03-03 | Seppic Sa | Composition of a live recombinant subunit vaccine and method of preparation. |
| WO1995011700A1 (en) * | 1993-10-29 | 1995-05-04 | Pharmos Corp. | Submicron emulsions as vaccine adjuvants |
| FR2733151B1 (en) * | 1995-04-20 | 1997-05-23 | Seppic Sa | THERAPEUTIC COMPOSITION COMPRISING AN ANTIGEN OR AN IN VIVO GENERATOR OF A COMPOUND COMPRISING AN AMINO ACID SEQUENCE |
| FR2754182B1 (en) * | 1996-10-07 | 1998-11-06 | Seppic Sa | NOVEL VACCINE COMPOSITIONS COMPRISING AS ADJUVANT A SYMPATHOMIMETIC COMPOUND |
-
2000
- 2000-06-09 FR FR0007408A patent/FR2809961B1/en not_active Expired - Fee Related
-
2001
- 2001-05-31 EP EP01401415A patent/EP1163909B1/en not_active Expired - Lifetime
- 2001-05-31 DE DE60136126T patent/DE60136126D1/en not_active Expired - Lifetime
- 2001-06-05 JP JP2001169177A patent/JP2002020314A/en not_active Withdrawn
- 2001-06-11 US US09/877,215 patent/US20020048587A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| FR2809961B1 (en) | 2004-12-03 |
| JP2002020314A (en) | 2002-01-23 |
| EP1163909A2 (en) | 2001-12-19 |
| EP1163909A3 (en) | 2002-02-06 |
| DE60136126D1 (en) | 2008-11-27 |
| US20020048587A1 (en) | 2002-04-25 |
| FR2809961A1 (en) | 2001-12-14 |
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